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Psen1  -  presenilin 1

Rattus norvegicus

Synonyms: PS-1, Presenilin-1, Protein S182, Psnl1
 
 
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Disease relevance of Psen1

 

Psychiatry related information on Psen1

 

High impact information on Psen1

  • Also present in the DIG fractions are the endoproteolytic fragments of presenilin-1 (PS1) and APP [7].
  • Par-4 expression was enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD [8].
  • Most cases of early-onset familial Alzheimer's disease (FAD) are caused by mutations in the genes encoding the presenilin 1 (PS1) and PS2 proteins, both of which undergo regulated endoproteolytic processing [9].
  • A familial Alzheimer's disease-associated PS-1 mutant, PS-1(L286V), causes a dramatic increase in T cell factor (TCF)/beta-catenin transcription in PC-12 cells, which prevents normal nerve growth factor (NGF)-induced neuronal differentiation and neurite outgrowth [10].
  • Additionally, through interactions with beta-catenin, PS-1 is associated with modulation of Wnt/beta-catenin signaling [10].
 

Chemical compound and disease context of Psen1

 

Biological context of Psen1

  • Detection of the presenilin 1 COOH-terminal fragment in the extracellular compartment: a release enhanced by apoptosis [12].
  • In addition, active sites of synaptogenesis, the base of the external granular layer and glomeruli, contained PS1 fragments and smaller amount of NCT [13].
  • Microinjection of plasmids expressing wild-type PS-1 or a PS-1 mutant with a deletion of exon 10 (PS1dE10) by themselves had no effect on the survival of primary SCG neurons [14].
  • Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-kappaB and stabilization of calcium homeostasis [15].
  • These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction [16].
 

Anatomical context of Psen1

 

Associations of Psen1 with chemical compounds

  • The apoptosis-enhancing action of mutant PS-1 was prevented by antioxidants (propyl gallate and glutathione), zVAD-fmk, and cyclosporin A, indicating requirements of reactive oxygen species (ROS), caspases, and mitochondrial permeability transition in the cell death process [18].
  • PC12 cell lines expressing a PS-1 mutation (L286V) exhibited increased sensitivity to apoptosis induced by 3-nitropropionic acid (3-NP) and malonate, inhibitors of succinate dehydrogenase, compared with control cell lines and lines overexpressing wild-type PS-1 [18].
  • PS1 protein accumulation was dose-responsive to NGF and required the presence of the TrkA NGF receptor tyrosine kinase [3].
  • An antagonist of voltage-dependent calcium channels (nifedipine), and a blocker of Ca2+ release from ER (dantrolene), counteract the adverse consequences of the PS-1 mutation [19].
  • PS mutation expressing astrocytes oscillated at lower ATP and glutamate concentrations when compared to wild-type PS1 expressing astrocytes [20].
 

Physical interactions of Psen1

  • Presenilin forms an active gamma-secretase complex together with Nicastrin (NCT), APH-1, and PEN-2, which among other substrates cleaves the beta-amyloid precursor protein (beta-APP) generating the amyloid beta-peptide and the beta-APP intracellular domain [6].
 

Co-localisations of Psen1

 

Regulatory relationships of Psen1

  • However, it is unclear how Notch cleavage and APP processing events which occur at or near the cell surface are influenced by PS1 [21].
  • Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function [16].
  • Presenilin-1 mRNA and beta-amyloid precursor protein mRNA are expressed in the developing rat olfactory and vestibulocochlear systems [22].
 

Other interactions of Psen1

  • Because PS1 has been associated with gamma-secretase activity, MOCA may be involved in the regulation of beta-amyloid precursor protein (APP) processing [23].
  • Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation [10].
  • Reports of PS1 localization to the endoplasmic reticulum (ER) and Golgi apparatus have focused attention on the early biosynthetic pathway as the site of PS1 function [21].
  • Previous studies have demonstrated the molecular linkage of three causative genes for early-onset Alzheimer's disease: the presenilin 1 gene on chromosome 14, the presenilin 2 gene on chromosome 1, and the amyloid precursor protein gene on chromosome 21 [24].
  • This study reveals the expressions of Alzheimer's disease-related amyloid precursor protein, presenilin-1, and a presynaptic marker protein, synaptophysin, in the archi-, paleo- and neocerebellum during the postnatal development of the rat [25].
 

Analytical, diagnostic and therapeutic context of Psen1

References

  1. Hypoxic remodelling of Ca2+ mobilization in type I cortical astrocytes: involvement of ROS and pro-amyloidogenic APP processing. Smith, I.F., Boyle, J.P., Green, K.N., Pearson, H.A., Peers, C. J. Neurochem. (2004) [Pubmed]
  2. Cloning of the cDNA encoding rat Presenilin-1. Taniguchi, T., Hashimoto, T., Taniguchi, R., Shimada, K., Kawamata, T., Yasuda, M., Nakai, M., Terashima, A., Koizumi, T., Maeda, K., Tanaka, C. Gene (1997) [Pubmed]
  3. The regulation of presenilin-1 by nerve growth factor. Counts, S.E., Lah, J.J., Levey, A.I. J. Neurochem. (2001) [Pubmed]
  4. Localization of presenilin-1 mRNA in rat brain. Quarteronet, D., Pradier, L., Czech, C., Delalonde, L., Burgevin, M.C., Doble, A., Petitet, F. Neuroreport (1996) [Pubmed]
  5. Expression of presenilin 1 mRNA in rat peripheral organs and brain. Nilsberth, C., Luthman, J., Lannfelt, L., Schultzberg, M. Histochem. J. (1999) [Pubmed]
  6. Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. Hansson, C.A., Frykman, S., Farmery, M.R., Tjernberg, L.O., Nilsberth, C., Pursglove, S.E., Ito, A., Winblad, B., Cowburn, R.F., Thyberg, J., Ankarcrona, M. J. Biol. Chem. (2004) [Pubmed]
  7. A detergent-insoluble membrane compartment contains A beta in vivo. Lee, S.J., Liyanage, U., Bickel, P.E., Xia, W., Lansbury, P.T., Kosik, K.S. Nat. Med. (1998) [Pubmed]
  8. Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Guo, Q., Fu, W., Xie, J., Luo, H., Sells, S.F., Geddes, J.W., Bondada, V., Rangnekar, V.M., Mattson, M.P. Nat. Med. (1998) [Pubmed]
  9. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Kim, T.W., Pettingell, W.H., Jung, Y.K., Kovacs, D.M., Tanzi, R.E. Science (1997) [Pubmed]
  10. Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Teo, J.L., Ma, H., Nguyen, C., Lam, C., Kahn, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. Mutant presenilin (A260V) affects Rab8 in PC12D cell. Kametani, F., Usami, M., Tanaka, K., Kume, H., Mori, H. Neurochem. Int. (2004) [Pubmed]
  12. Detection of the presenilin 1 COOH-terminal fragment in the extracellular compartment: a release enhanced by apoptosis. Benussi, L., Alberici, A., Mayhaus, M., Langer, U., Ghidoni, R., Mazzoli, F., Nicosia, F., Barbiero, L., Frisoni, G., Zanetti, O., Gasparini, L., Nitsch, R.M., Binetti, G. Exp. Cell Res. (2001) [Pubmed]
  13. Transient abundance of presenilin 1 fragments/nicastrin complex associated with synaptogenesis during development in rat cerebellum. Uchihara, T., Sanjo, N., Nakamura, A., Han, K., Song, S.Y., St George-Hyslop, P., Fraser, P.E. Neurobiol. Aging (2006) [Pubmed]
  14. Presenilin-1 protects against neuronal apoptosis caused by its interacting protein PAG. Zhou, Y., Zhang, W., Easton, R., Ray, J.W., Lampe, P., Jiang, Z., Brunkan, A.L., Goate, A., Johnson, E.M., Wu, J.Y. Neurobiol. Dis. (2002) [Pubmed]
  15. Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-kappaB and stabilization of calcium homeostasis. Guo, Q., Robinson, N., Mattson, M.P. J. Biol. Chem. (1998) [Pubmed]
  16. Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function. Guo, Q., Christakos, S., Robinson, N., Mattson, M.P. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  17. Normal distribution of presenilin-1 and nicastrin in skeletal muscle and the differential responses of these proteins after denervation. Sakuma, K., Nakao, R., Yamasa, Y., Yasuhara, M. Biochim. Biophys. Acta (2006) [Pubmed]
  18. Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. Keller, J.N., Guo, Q., Holtsberg, F.W., Bruce-Keller, A.J., Mattson, M.P. J. Neurosci. (1998) [Pubmed]
  19. Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide. Guo, Q., Furukawa, K., Sopher, B.L., Pham, D.G., Xie, J., Robinson, N., Martin, G.M., Mattson, M.P. Neuroreport (1996) [Pubmed]
  20. Calcium oscillations in type-1 astrocytes, the effect of a presenilin 1 (PS1) mutation. Johnston, J.M., Burnett, P., Thomas, A.P., Tezapsidis, N. Neurosci. Lett. (2006) [Pubmed]
  21. Endogenous presenilin-1 targets to endocytic rather than biosynthetic compartments. Lah, J.J., Levey, A.I. Mol. Cell. Neurosci. (2000) [Pubmed]
  22. Presenilin-1 mRNA and beta-amyloid precursor protein mRNA are expressed in the developing rat olfactory and vestibulocochlear systems. Utsumi, M., Sato, K., Tanimukai, H., Kudo, T., Nishimura, M., Takeda, M., Tohyama, M. Acta Otolaryngol. (1998) [Pubmed]
  23. A novel mechanism for the regulation of amyloid precursor protein metabolism. Chen, Q., Kimura, H., Schubert, D. J. Cell Biol. (2002) [Pubmed]
  24. Proteolytic fragments of Alzheimer's disease-associated presenilin 1 are present in synaptic organelles and growth cone membranes of rat brain. Beher, D., Elle, C., Underwood, J., Davis, J.B., Ward, R., Karran, E., Masters, C.L., Beyreuther, K., Multhaup, G. J. Neurochem. (1999) [Pubmed]
  25. Expressions of amyloid precursor protein, synaptophysin and presenilin-1 in the different areas of the developing cerebellum of rat. Fakla, I., Kovacs, I., Yamaguchi, H., Geula, C., Kasa, P. Neurochem. Int. (2000) [Pubmed]
  26. Presenilin-1 is located in rat mitochondria. Ankarcrona, M., Hultenby, K. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  27. In situ hybridization analysis of presenilin 1 mRNA in Alzheimer disease and in lesioned rat brain. Page, K., Hollister, R., Tanzi, R.E., Hyman, B.T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
 
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